Sensory cues can be attractive or repulsive depending on the context in which they are present. To make contextually appropriate decisions, the brain must integrate sensory information in the environment with its own internal needs. Biogenic amines are small molecules that the brain releases that cause changes in neural circuit function and drive contextually appropriate behavior. Dopamine release encodes motivation and salience and regulates reward-driven behaviors. In humans, regulation of dopamine signaling is critical: too much dopamine signaling is implicated in schizophrenia, whereas decreased dopamine signaling is implicated in Parkinson's Disease. How dopamine dynamically modulates neural circuits to effect state-dependent changes on behavior is poorly understood. The experiments in this proposal will investigate how dopamine acts at the gene, cell, and circuit levels to alter CO2 response behavior as a function of starvation in C. elegans. We have found that, when fed, C. elegans adults avoid CO2, an evolutionarily advantageous strategy that may allow them to evade CO2-emitting predators. Within 3 hours of starvation, worms switch from avoiding CO2 to being attracted to it. We have implicated a role for dopamine in this switch. Worms with no dopamine are constitutively attracted to CO2 and worms with increased dopamine have attenuated attraction to CO2 even when starved. We have identified a dopamine receptor that is involved in mediating the switch from CO2 avoidance to attraction. We will investigate how dopaminergic signaling regulates CO2-evoked behavior using pharmacogenetics, quantitative worm tracking, and time-lapse imaging of dopaminergic neuron activity (Aim 1). We will then dissect how dopamine functionally alters the CO2 microcircuit by imaging activity of CO2 circuit neurons in wild-type worms and mutants with altered dopaminergic signaling (Aim 2). Finally, we will take a systems-based approach to image and perturb neural circuit function in intact, freely moving animals to determine how dopamine-mediated changes in neuronal activity directly translate to observable changes in behavior (Aim 3). These experiments will provide fundamental insights into how dopamine dynamically modulates neuronal circuits and may elucidate how dysregulation of dopaminergic signaling leads to sensory deficits seen in neuropsychiatric disease.